Immunosuppressive therapy post-transplantation in children: what the clinician needs to know

ABSTRACT

Introduction: The goal of immunosuppressive therapy post-transplantation in pediatric renal transplant recipients is to prevent acute and chronic rejection while minimizing drug side effects. Most therapies alter immune response mechanisms but are not immunologically specific, and a careful balance is required to find the dose that prevents rejection of the graft, while minimizing the risks of over-immunosuppression leading to infection and cancer.

Areas covered: This review article focuses on immunosuppressive therapy in pediatric renal transplant recipients, but many aspects can be applied on pediatric recipients of other solid organ transplants such as liver and heart. The major maintenance immunosuppressive agents currently used in various combination regimens are tacrolimus, cyclosporine, mycophenolate mofetil, azathioprine, everolimus, sirolimus, and glucocorticoids.

Expert opinion: Although data from adult renal transplantation trials are used to help guide management decisions in pediatric patients, immunosuppressive therapy in pediatric renal transplant recipients often must be modified because of the unique dosage requirements and clinical effects of these agents in children, including their impact on growth and development. The optimal immunosuppressive therapy post-transplant is not established. The goal remains to find the best combination of immunosuppressive agents that optimizes allograft survival by preventing acute rejection while limiting drug toxicities.

KEYWORDS:

• Calcineurin inhibitors
• cyclosporine
• everolimus
• glucocorticoids
• immunosuppressive induction therapy
• immunosuppressive maintenance therapy
• mycophenolate mofetil
• pediatric renal transplantation
• tacrolimus

Article highlights

• The common immunosuppressive agents used in pediatric renal transplantation include antibodies to cell surface antigens on lymphocytes (anti-thymocyte globulin (ATG)), anti-interleukin 2 (IL-2) receptor antibodies, the calcineurin inhibitors tacrolimus and cyclosporine, the lymphocyte proliferation inhibitors mycophenolate mofetil (MMF) and azathioprine, the mammalian target of rapamycin (mTOR) inhibitors sirolimus and everolimus and glucocorticoids.

• The optimal prophylactic induction immunosuppressive therapy remains controversial. Induction therapy with thymoglobulin produces the greatest benefits in groups at high risk for allograft rejection, such as African-Americans, recipients of kidneys with prolonged cold ischemia time, and those at high immunologic risk, particularly individuals who are presensitized.

• Although an adequate maintenance level of immunosuppression is required to dampen the immune response to the allograft, the level of chronic immunosuppression is slowly decreased over time to help lower the overall risk of infection and malignancy; these risks directly correlate with the degree of overall immunosuppression. Maintenance regimens consist of a combination of immunosuppressive agents that differ in their mechanism of action. This strategy minimizes morbidity and mortality associated with each class of agent while maximizing overall effectiveness.

• Allograft survival rates vary among the various immunosuppressive agents due to patient-specific clinical characteristics, such as age, obesity, ethnicity, hyperlipidemia, arterial hypertension, and/or delayed allograft function. Immunosuppressive agents should therefore be chosen in part based on patient characteristics. Other issues to be taken into account are related to the immunologic history of the patient, such as the degree of HLA matching, pre-sensitization, re-transplant, history of acute rejection episodes and the risk of recurrent disease.

• Current immunosuppressive agents reduce acute rejection, but do not induce tolerance. A few patients with organ transplants successfully can withdraw their immunosuppression without rejecting their grafts for long periods of time. However, these are rare exceptions, and such patients may eventually reject, even after years. Much additional work is needed to define optimal immunosuppressive regimens in pediatric renal transplant patients, particularly with respect to newer and evolving regimens. The safety and efficacy of these protocols with special emphasis on long-term graft survival and PTLD need to be established.

Declaration of interest

B Tönshoff has received travel grants from Alexion, Astellas, Novartis, and Roche, grant/research support from Astellas, Lilly, Novartis, Novo Nordisk, and Roche, has acted as a consultant to Bristol‐Myers Squibb, Novartis, and Raptor, and received honoraria from Astellas, Bristol‐Myers Squibb, and Novartis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.